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PTPN2 Expression Is Associated with Inferior Molecular Response in De-Novo Chronic Myeloid Leukaemia Patients

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PTPN2 Expression Is Associated with Inferior Molecular Response in De-Novo Chronic Myeloid Leukaemia Patients Letters to the Editor 702 CONFLICT OF INTEREST 4 Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z et al. The authors declare no conflict of interest. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650–1653. 5 Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D et al. beta- ACKNOWLEDGEMENTS Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010; 18: 606–618. This work was supported in part by the National Cancer Institute (CA66996 and 6 Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al. Loss of beta-catenin CA140575) and the Leukemia and Lymphoma Society. DK was supported by NIH impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007; 12: NIDDK award K01DK092300. 528–541. 7 Cobas M, Wilson A, Ernst B, Mancini SJ, MacDonald HR, Kemler R et al. 1 2 2 1 2 CEL Ng , A Sinha , A Krivtsov , S Dias , J Chang , Beta-catenin is dispensable for hematopoiesis and lymphopoiesis. J Exp Med 2004; SA Armstrong1,2 and D Kalaitzidis1,3 199: 221–229. 1Division of Hematology/Oncology, Children’s Hospital Boston and 8 Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hemato- Dana-Farber Cancer Institute, Harvard Medical School and the logic malignancies. Blood 2012; 120: 3397–3406. Harvard Stem Cell Institute, Boston, MA 02115, USA 9 Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J et al. Somatic E-mail: [email protected] or [email protected] activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal 2 myeloproliferative disorder. Proc Natl Acad Sci USA 2004; 101: 597–602. Current Address: Human Oncology and Pathogenesis Program, 10 Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H et al. Conditional Memorial Sloan Kettering Cancer Center, New York, expression of oncogenic K-ras from its endogenous promoter induces a myelo- NY 10065, USA. proliferative disease. J Clin Invest 2004; 113: 528–538. 3 Current Address: Department of Medicine, Center for Regenerative 11 Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, Hermiston ML et al. Medicine, Massachusetts General Hospital, Harvard Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol 2009; Medical School, Boston, MA 02114, USA. 7: e59. 12 Gandillet A, Park S, Lassailly F, Griessinger E, Vargaftig J, Filby A et al. Heterogeneous sensitivity of human acute myeloid leukemia to beta-catenin REFERENCES down-modulation. Leukemia 2011; 25: 770–780. 1 Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M et al. 13 Krivtsov AV, Figueroa ME, Sinha AU, Stubbs MC, Feng Z, Valk PJ et al. Cell of origin Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion. determines clinically relevant subtypes of MLL-rearranged AML. Leukemia 2013; Cell Stem Cell 2011; 9: 345–356. 27: 852–860. 2 Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L et al. Genetic and phar- 14 Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. macologic inhibition of beta-catenin targets imatinib-resistant leukemia stem Clonal evolution of preleukemic hematopoietic stem cells precedes human acute cells in CML. Cell Stem Cell 2012; 10: 412–424. myeloid leukemia. Sci Transl Med 2012; 4: 149ra118. 3 Guo W, Lasky JL, Chang CJ, Mosessian S, Lewis X, Xiao Y et al. Multi-genetic events 15 Christopherson 2nd KW, Hangoc G, Mantel CR, Broxmeyer HE. Modulation of collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305: 2008; 453: 529–533. 1000–1003. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Elevated PTPN2 expression is associated with inferior molecular response in de-novo chronic myeloid leukaemia patients Leukemia (2014) 28, 702–705; doi:10.1038/leu.2013.329 expression was measured using the Affymetrix Human Gene 1.0 ST microarray, as previously described.6 Briefly, analysis of the microarray data included normalisation by Robust multi-array Chronic myeloid leukaemia (CML) is characterised by the average (RMA) using the aroma.affymetrix package, with custom t(9;22)(q34;q11) translocation, resulting in the Bcr-Abl oncoprotein annotation (Brainarray Entrez Gene 16.0), in the R statistical which can be targeted by tyrosine kinase inhibitors (TKIs). program (v2.15.1). Event-free survival (EFS) and mutation-free However, the clinical response to TKIs between patients is highly survival (MFS) were calculated by the Kaplan–Meier method using variable. Protein tyrosine phosphatase, non-receptor type 2 SPSS statistical software (IBM Corporation, Armonk, NY, USA). (PTPN2) is a member of the protein tyrosine phosphatase family. Molecular responses were calculated by cumulative incidence PTPN2 gene expression is associated with ‘stemness’ across the using a Fine and Gray model implemented in the R package haematopoietic stem cell, embryonic stem cell and neural stem ‘cmprsk’, and by multivariate Cox regression analysis. In the cell subpopulations.1 PTPN2 has also been shown to regulate the competing risk regression models, an event was defined by functions of Bcr-Abl and c-Abl,2 as well as the phosphorylation achievement of the desired response, while cessation of status of STAT13 and STAT5.4 Previous studies have demonstrated TKI for any reason (including death) was the competing risk. that reduced PTPN2 expression is associated with resistance to All further statistical analyses were performed using GraphPad imatinib, but sensitivity to interferon-alpha in a BCR-ABL1 þ cell Prism v6.0. line, KT-1.5 However, no studies have been performed The total patient cohort was separated into two groups based investigating PTPN2 expression in primary CML patient samples. on PTPN2 expression. High PTPN2 expression (n ¼ 23) was defined Therefore, we sought to investigate the impact of PTPN2 as the top 25% (PTPN2 expression X7.78), whereas patients with expression on clinical response in a cohort of de-novo PTPN2 expression o7.78 were defined as low PTPN2 expression chronic-phase CML (CP-CML) patients. (n ¼ 70). Next, we investigated the association between PTPN2 A total of 93 mRNA samples, prepared from patient mono- expression and clinical outcome. Data from 71 patients treated nuclear cells (MNCs) isolated from blood collected at diagnosis in Adelaide (with response data available) under the imatinib (prior to imatinib treatment), were analysed. PTPN2 gene treatment protocol were available for analysis. However, only 70 Accepted article preview online 6 November 2013; advance online publication, 22 November 2013 Leukemia (2014) 694 – 725 & 2014 Macmillan Publishers Limited Letters to the Editor 703 patients had 24-month follow-up data available. Surprisingly, high (Po0.05) and STAT4 (Po0.0001), and significantly decreased PTPN2 expression (X7.78) was associated with a decreased expression of STAT3 (Po0.0001), but not STAT6, was also observed achievement of major molecular response (MMR; o0.1% BCR- in the high PTPN2 expression patient group (Supplementary ABL1 transcript) by 24 months (33.3%), compared with the low Figures 1A–E). A significant increase in JAK1 (Po0.05) and PTPN2 expression (o7.78) patient group (74.2%, P ¼ 0.025; JAK3 (Po0.001), and a significant decrease in JAK2 (Po0.05) Figure 1a). This result was unexpected, as Nishiyama-Fujita mRNA expression was also observed in the high PTPN2 expression et al.5 previously demonstrated that knockdown of PTPN2 patient group, compared with the low PTPN2 expression sensitised the KT-1 cell line to imatinib-induced cell death. patient group (Supplementary Figures 2A–C). These results suggest However, their result was limited to only one cell line. No a possible link between JAK/STAT gene expression and PTPN2 statistical significance was observed for other response in CML. parameters, including complete molecular response (o0.000032% We also investigated alternative signalling pathways that may BCR-ABL1 transcript) by 24 months (P ¼ 0.64), EFS (P ¼ 0.69) or MFS be activated in the high PTPN2 expression group, associated with (P ¼ 0.29; data not shown). We observed no correlation between poor MMR rates. There were 1409 genes identified with high PTPN2 expression and EFS or MFS, likely due to the limited statistically significant differences between the low (n ¼ 58) and patient numbers associated with these events. Similarly, we were high PTPN2 expression (n ¼ 12) patient groups (false discovery rate unable to analyse transformation-free survival in relation to PTPN2 (FDR) Po0.05, fold change 41.5, Supplementary Table 2). gene expression due to only one patient in this cohort later Interestingly, b-catenin, ABCB1 and YES1 were significantly transforming to blast crisis (BC). Furthermore, there was no upregulated in patients with high PTPN2 expression (FDR significant association between PTPN2 expression and early Po0.05; Figure 2a). Gene-set enrichment analysis (GSEA) was molecular response based on 3-month BCR-ABL1 mRNA transcript then performed, using the curated data set from the molecular levels (o10% BCR-ABL1, P ¼ 0.99; data not shown). The Sokal risk signature database (MSigDB v4.0, Broad Institute, Cambridge, MA, score also had no significant association with PTPN2 expression USA) and SABioscience pathway database, to investigate signal- (P ¼ 0.82; data not shown). In addition, there was no significant ling pathways associated with the high PTPN2 expression patient association between gender and PTPN2 expression (P ¼ 0.45; data group. As shown in Figure 2b, GSEA revealed that STAT5A, WNT/b- not shown). However, a lower white cell count (WCC) was catenin and stem cell signalling were enriched (FDR qo0.05) in significantly associated with high PTPN2 expression, compared patients with high PTPN2 expression.
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